The optimal second-line therapy for patients with advanced biliary tract cancer (BTC) remains unclear as current second-line treatment options, including FOLFOX and S-1, have modest clinical benefit with limited overall response rates (ORRs) and suboptimal median overall survival (OS).1-3 Targeted therapies are of increasing interest as a second-line treatment option for certain patients with actionable mutations, including HER2.4 HER2 overexpression or amplification is prevalent in up to almost 20% of patients with BTC, and some case studies and single-arm prospective studies have suggested therapeutic potential with HER2-targeted therapy.1,4 Tucatinib is a HER-selective oral tyrosine kinase inhibitor currently approved for HER2-positive metastatic breast cancer and metastatic colorectal cancer following progression on previous therapy.5 At the ASCO 2023 annual meeting, Yoshiaki Nakamura, MD, PhD, presented results from SGNTUC-019 (NCT04579380), which investigated tucatinib and trastuzumab in patients with previously treated HER2-positive metastatic BTC.6
SGNTUC-019 is an open-label, phase 2 basket study that investigated the antitumor activity and safety of tucatinib and trastuzumab in patients with HER2-altered solid tumors.6 To be enrolled, patients had to have unresectable locally advanced or metastatic cancer previously treated with ≥1 prior lines of therapy; however, no history of HER2-directed treatment was also required.6 Cohort 3 consisted of patients with BTC who had HER2 overexpression or amplification.6 Patients were treated on a 21-day cycle with tucatinib 300 mg orally twice a day and trastuzumab intravenously every 3 weeks.6 The primary end point was confirmed ORR, and key secondary end points included safety, disease control rate (DCR), duration of response (DOR), progression-free survival (PFS), and OS.6
A total of 30 patients with BTC were enrolled, all of whom received ≥1 doses of tucatinib or trastuzumab.6 The mean study follow-up was 10.8 months. Of the 30 patients, 8 had extrahepatic cholangiocarcinoma (CCA), 7 had intrahepatic CCA, and 15 had gallbladder cancer.6 Patients had an average of 2 prior lines of therapy in any setting.6 The confirmed ORR was 46.7%, 1 patient had a complete response, and 13 had a partial response.6 The median DOR was 6 months, the median time to first response was 2.1 months, the DCR was 76.7%, and 70% of patients had a reduction in tumor size.6 The median PFS was 5.5 months and median OS was 15.5 months.6 All patients had ≥1 treatment-emergent adverse event (TEAE), 18 patients had a TEAE grade ≥3, and 13 patients had a serious TEAE.6 Most grade ≥3 and serious TEAEs were not related to tucatinib (7 patients with tucatinib-related grade ≥3 TEAEs, 3 patients with tucatinib-related serious AEs).6 The most common grade ≥3 TEAEs were nausea, decreased appetite, and cholangitis, each in 3 patients.6 In addition, 3 patients had a TEAE leading to discontinuation of any study treatment (3 tucatinib, 1 trastuzumab), and there were no TEAEs leading to death.6
Overall, this study demonstrated antitumor activity with tucatinib and trastuzumab in patients with previously treated HER2-positive BTC, with an ORR of 46.7%.6 The combination of tucatinib and trastuzumab was well tolerated with low rates of discontinuation and no treatment-related deaths.6 Results from this study further validate that HER2 is an actionable target in certain patients with BTC and should be explored further in larger studies.
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